Abstract: There are several criteria by which the success or failure of implantable materials can be measured; but, without question, the manner in which the host responds to the implanted material will be a critical determinant of outcome. Largely, the interaction of immune cells with implanted materials has been considered a precursor to the foreign body reaction with associated negative impacts upon functionality. Recently, the role of the innate immune system, particularly that of macrophages, in the host response to biomaterials has received renewed attention. It has now been shown that macrophages, depending upon highly plastic and context- dependent polarization profiles (i.e. M1 pro-inflammatory vs. M2 anti-inflammatory/regulatory), are also capable of affecting positive outcomes following biomaterial implantation. This emerging understanding of the essential constructive and regulatory roles of macrophages in positive outcomes represents a significant departure from the classical paradigms of host biomaterial interactions. It now appears desirable that emerging biomaterials-based approaches to tissue reconstruction should not only accommodate but also promote involvement of the immune system to facilitate positive outcomes. However, such approaches cannot be developed without a detailed understanding of both the contributions of individual macrophage subtypes to tissue remodeling and integration and the context in which host encounters the implant. The present proposal seeks to develop a comprehensive and integrated approach to broadening the current understanding of how macrophages, their functional subsets, and host characteristics affect the host response to biomaterials. The proposed work builds upon our previous studies demonstrating that macrophage M1/M2 polarization at early time points is predictive of downstream integration outcomes and that the implantation microenvironment (i.e. tissue type, age, disease status) strongly affects the host response and subsequent tissue remodeling outcomes. Additionally, we have developed a number of model systems for assessing the specific contributions of M1 and M2 macrophages in the host response to biomaterials and novel methods for the modulation of the host response at the biomaterial surface. Collectively, these studies will provide crucial insight into the use of biomaterials as implants and provide methods for promoting improved outcomes associated with their use. .